Drug administration

ABSTRACT

Compositions and methods useful for the prevention or treatment of a human or animal disorder or for the regulation of the human or animal physiological condition are provided. The compositions used comprise, in admixture, a biologically-effective amount of a drug specific for the disorder or condition and a biocompatible, water-soluble, amphiphilic steroid, other than a natural bile salt, which is capable of increasing drug permeability of the human or animal body surface across which the drug is to be administered, in an amount effective to increase the permeability of the surface to the drug.

Part of the work described and claimed herein was supported in part by agrant or award from the United States Government, which has certainrights in the invention.

The application is a continuation of Ser. No. 614,115, 05/25/84, nowU.S. Pat. No. 4,746,508 which is a continuation-in-part of applicationSer. No. 501,187, filed Jun. 6, 1983, now U.S. Pat. No. 4,548,922entitled "Drug Administration," which is incorporated herein byreference.

INTRODUCTION

This invention relates to the administration of drugs across human oranimal body surfaces. (As used herein, the term "drug" is defined as anybiologically-active chemical or natural substance useful for treating amedical or veterinary disorder, preventing a medical or veterinarydisorder, or regulating the physiology of a human being or animal). Moreparticularly, the invention relates to an administration method based onthe use of biocompatible, water-soluble, amphiphilic steroids capable ofincreasing the permeability of human and animal body surfaces to avariety of biologically-active substances. Application of admixtures ofsteroid and drug to mucosal or epithelial surfaces advantageouslyresults in enhanced drug delivery across the body surface.

BACKGROUND OF THE INVENTION

To elicit its characteristic biological response in the body, a drugmust be available in an effective concentration at its site of action.The concentration of a drug that reaches its reactive site varies withsuch factors as the amount of drug administered, the extent and rate ofits absorption, distribution, binding or localization in tissues, itsbiotransformation, and its excretion. (For a review of these topics, seeGoodman and Gilman's, The Pharmacological Basis of Therapeutics, 6thedition, MacMillan Publishing Co., Inc., New York, 1980, pp. 1-39. ) Theforegoing factors, and hence the ultimate efficacy of a particular drug,are in turn influenced by the route chosen for drug administration.

The common routes of drug administration are enteral (oral ingestion)and parenteral (intravenous, subcutaneous, and intramuscular) routes ofadministration. To determine the appropriate mode of drugadministration, it is necessary to understand some of the advantages anddisadvantages of the route used. For example, intravenous drugadministration is advantageous for emergency use when very rapidincreases in blood levels are necessary. The intravenous route allowsfor dosage asjustments when required, and is also useful foradministration of large volumes of a drug when diluted. However, thereare limitations on the usefulness of intravenous drug administration.One problem is the risk of adverse effects resulting from the rapidaccumulation of high concentrations of the drug in plasma and tissues.Consequently, intravenously administered drug solutions must generallybe continuously monitored and injected slowly. The intravenous route isnot suitable for oily or insoluble substances. Furthermore, intravenousadministration is restricted to trained medical personnel.

Other routes of parental administration are often inconvenient orpainful for patients especially if frequent administration is required.Subcutaneous injection is used for drugs that are not irritating. Thismode of administration is not suitable for delivering large volumes noris it suitable for administering irritating substances which may causepain of necrosis at the site of injection. Intramuscular administrationis generally suitable for moderate volumes, oily substances, and someirritating substances. The intramuscular route cannot be used duringanticoagulant medication and may interfere with the interpretation ofcertain diagnostic tests.

Oral administration of drugs is generally more convenient and economicaland is most acceptable to humans. However, this route of administrationrequires patient cooperation. Absorption may be inefficient (i.e.,incomplete) for poorly soluble, slowly absorbed, or unstable drugpreparations, and the time from ingestion to absorption may prohibiteffective use in emergency situations. Furthermore, peptides andproteins will often be destroyed by the digestive enzymes, acid, andsurface-active lipids in the gut prior to reaching the site of action.

Certain drugs which need to be administered frequently are noteffectively absorbed when administered orally and hence must bedelivered by injection methods. Yet, a number of problems are associatedwith conventional injection therapies.

By way of illustration, conventional insulin therapy requires frequentinsulin injections resulting in discomfort and disruption of thepatient's lifestyle. Hence, many diabetics either refuse insulin therapyaltogether or avoid intensive treatment regimens such as those whichinvolve injections with each meal. In addition, certain patients,especially young children, elderly patients, and those who are blindand/or disabled, often have difficulty with insulin self-administrationby injection. Furthermore, insulin absorption after subcutaneousinjection is variable in terms of rate and amount depending upon factorssuch as exercise, local blood flow, depth and volume of injection, thepresence of local proteases which degrade insulin, and perhaps other,unknown factors. Even presently available short acting and long actingpreparations of insulin or mixtures thereof cannot mimic the dailyglucose and insulin excursions of non-diabetic individuals. Portableinfusion pumps have now been employed to increase the ease of deliveringsubcutaneously meal-related insulin boluses. However, these devices areexternally worn and are therefore cumbersome. They require regularneedle replacement, are complicated by local infections at the site ofneedle placement, are expensive, and are not acceptable to manypatients.

It is clear that a reproducible, reliable, and non-invasive means fordelivering drugs such as insulin would be highly desirable. What isneeded especially in the case of insulin is a delivery system that wouldpermit easy, rapid, and non-invasive administration of insulin at mealtimes when blood glucose concentration rises to peak levels. Since thediscovery of insulin six decades ago, there have been many attempts todevelop alternate means of insulin delivery. For instance, insulin hasbeen administered enternally, either alone or encapsulated in liposomes(microcapsules), sublingually, vaginally, and rectally, with and withoutsurfactants.

In addition to the preceding routes of administration, the nasal routehas been the subject of investigation for the delivery not only ofinsulin but of other drugs as well. It is known that certain very smallpeptides can be absorbed through the nasal mucosa as a "snuff" ordirectly from aqueous solution without an adjuvant. Examples of peptideswhich can sometimes be administered by this route areadrenocorticotrophic hormone (ACTH), luteinizing hormone releasinghormone (LHRH), oxytocin and vasopressin. Indeed, for patients withdiabetes insipidus, the intranasal route is frequently the means forvasopressin delivery.

In constrast to these directly administrable compounds, many drugs suchas insulin are inefficiently absorbed across mucous membranes atphysiological pH in the absence of adjuvants. Several workers haveattempted to mix insulin with adjuvants that might enhance nasal insulinabsorption. Hirai et al., Int. J. Pharmaceutics (1981) 9:165-184; Hiraiet al., Diabetes (1978) 27:296-299; British Pat. No. 1,527,605; and U.S.Pat. No. 4,153,689; and Pontiroli et al. (1982) Br. Med J. 284:303-386,have described the use of various bile salts to enhance absorption ofinsulin by the nasal mucosa

While the nasal mucosal route has received considerable attention forsystemic drug delivery, it has also hitherto been known that drugs maybe applied to mucous membranes of the conjunctiva, nasopharynx,oropharynx, ear canal, respiratory tract, vagina, rectum, colon, andurinary bladder for their local effects.

SUMMARY OF THE INVENTION

We have discovered an effective means of administering a drug to a humanbeing or animal which avoids many of the problems associated with othermodes of administration such as injection. The invention providesmethods and compositions useful for the prevention and/or treatment ofhuman or animal disorders and for the regulation of aspects of human oranimal physiology, e.g., fertility. The compositions employed areadmixtures comprising: (a) as active ingredient, a drug specific for agiven disorder or condition in a biologically-effective amount; and (b)as adjuvant, a biocompatible, water-soluble, amphiphilic steroid, otherthan a natural bile salt, capable of increasing drug permeability of ahuman or animal body surface across which the drug is to beadministered, in an amount effective to increase the permeability ofsaid surface to said drug. The admixtures can be applied advantageouslyto such body surfaces as mucosal and epithelial surfaces to achieveimproved drug transport across the surfaces, thereby enhancing thedelivery of the drug to its ultimate site of action in the body.

Preferably the steroid adjuvant is one of the naturally occurringsteroids, fusidic acid or cephalosporin P₁, P₂, P₃, P₄ or P₅ or aderivative of any of these. The steroid may have the following formula:##STR1## wherein each dashed line, independently, represents a single ora double bond; D is a group which renders an effective amount of thesteroid water soluble within the range of about pH 2 to about pH 12; Eand G are individually OAc, OH, or a lower alkyl or lower heteroalkyl; Wis OAc or H; and Q, V and X are individually OH or H. Most preferablythe steroids of formula (1) have functional groups as follows: E is βOAc, α OH, or a lower (3 or fewer carbons) alkyl or heteroalkyl group inβ position; G is α OAc, OH, lower alkyl, or lower heteroalkyl; W is αOAc or H; Q is OH or H, provided that, when W is α OAc and Q is α OH, Qmust be α-axial; V is H or α OH; and X is H or α OH; provided that thesteroid contains two or three polar functions exclusive of D. Three OHgroups are allowed provided that one is C₁₆ α-axial, replacing OAc atthat position. (As used herein, the symbol "OAc" refers to the acetoxylradical OCOCH₃.)

The steroid of formula (1 ) can be unconjugated, i.e., D is O⁻ Na⁺, O⁻K⁺, O⁻ Rb⁺, O⁻ Cs⁺, or some other ionic configuration, or it can beconjugated, i.e., D is an organic group containing at least one carbonatom. Preferably group D has a molecular weight below about 600 daltonsand is one of the following groups:

(a) a peptide of one, two, or three amino acids and containing an ionicfunction which is dissociated within the range of about pH 2 to about pH12;

(b) a heteroalkyl group of about three or fewer carbon atoms whichcontains an ionic function which is dissociated within the range ofabout pH 2 to about pH 12;

(c) a uronic acid of about six or fewer carbon atoms which contains anionic function which is dissociated within the range of about pH 2 toabout pH 12;

(d) a polyether containing between about six and about fourteen carbonatoms, inclusive, which terminates in an ionic function which isdissociated within the range of about pH 2 to about pH 12; or

(e) a polyether containing between about sixteen and about twenty-fourcarbon atoms, inclusive, and optionally terminating in an ionic functionwhich is dissociated within the range of about pH 2 to about pH 12.

Group D is preferably bonded to C₂₁ via an amide or ester linkage.

Preferably the steroid used in the invention is characterized in thatthe unconjugated derivative of the steroid is retained on hydrophobiccolumn for a length of time sufficient to produce a k' factor value ofat least about 4, the k' factor value being obtained by subjecing amonomeric solution of 1 mg/ml of such steroid derivative tohigh-performance liquid column chromatography at 3,000 psi, using a250×4.6 mm column having octadecylsilane-coated 5 μm silica particles asthe stationary phase and a mobile phase, delivered at 1.0 ml/min.,consisting of 75% methanol in water, v/v, buffered with 0.005 M KH₂ PO₄/H₃ PO₄ to give an apparent pH value, as measured using a glasselectrode, of 5.0, the k' factor value being defined by k'=(t_(r)-t₀)/t₀, where t₀ is the retention time in the column of the solventfront and t_(r) is the retention time in the column of the steroidderivative as measured by obtaining the elution profile of the steroidderivative by absorbance at 210 nm.

Preferably the steroid is further characterized in that the criticalmicellar temperature (CMT) (the temperature at which the steroid ceasesto be an insoluble crystal or gel and begins to go into solution andself-associate in solution) of an aqueous 1% solution, w/v, of thesteroid is below human or animal body temperture, and optimally belowabout 0° C. within the range of about pH 2 to about pH 12 (a measure ofsolubility); and the critical micellar concentration (CMC) (theconcentration at which the steroid ceases to be an ideal solution andbegins to self-associate) is as high as 8 mMolar but preferably lessthan 4 mM and more preferably less than 2 mMolar at 37° C. in 0.15 MNaCl as measured by surface tension.

Preferred steroids are ionized or partially ionized alkali salts offusidic acid, 24,25-dihydrofusidic acid, cephalosporin P₁ and C₂₁conjugates of these; and tauro-24,25-dihydrofusidate andglyco-24,25-dihydrofusidate. Other preferred steroids may be17,20-24,25-tetrahydrofusidic acid, 3-acetoxyl-fusidic acid,cephalosporin P₂ -P₅, and C₂₁ conjugates of these; andtauro-17,20-24,25-tetrahydrofusidate,tauro-16α-OH-24,25-dihydrofusidate,tauro-16α-OH-17,20-24,25-tetrahydrofusidate,tauro-16-O-methyl-ether-24,25-dihydrofusidate,tauro-16-O-methyl-ether-17,20-24,25-tetrahydrofusidate. The foregoingpreferred steroids must be freely soluble in water at the pH of thecomposition to be administered. A broad spectrum of drugs may be usedincluding but not limited to (a) peptides and polypeptides which have amolecular weight between about 100 and about 300,000 daltons, (b)non-peptides, and (c) other drugs.

The invention permits more effective, safer and convenientadministration across a body surface of a human being or animal, e.g.,any mucosal surface, including but not limited to oropharynx, ear canal,respiratory tract, nasopharynx, conjunctiva, rectal, gastric,intestinal, endometrial, cervical, vaginal, colon, urethra, urinarybladder, and tympanic membrane, of a wide range of drugs, some of whichnormally cannot be so administered. For example, in contrast tointravenous injection, the invention allows for convenient patientself-administration of drugs, making it more likely that the patientwill adhere to prescribed treatment schedules. The invention willdeliver drugs more quickly than oral, subcutaneous, or intramuscularadministration and is potentially more effective in delivering drugs toa localized site than is intravenous administration. In contrast to oraladministration, drugs administered by the method of the presentinvention do not need to pass through the liver where they might bemetabolized in order to reach the site of action, in some cases reducingliver toxicity. Because drugs can be delivered more efficiently to thesite of action or into the blood stream, in many cases a higherpercentage of a given drug will reach the site than when administered byother means, thereby reducing the quantity of the drug that needs to beadministered. Administration of reduced, quantities of drug can be morecost effective than administration of the same drug by a conventionalmethod. Alternatively, this method provides a means for deliveringincreased amounts of drug to a site, if desired or necessary. Inaddition, administration, according to the present invention, does nothave deleterious toxic side effects. In particular, the steroids of theinvention are able to potentiate the transport and enhance absorption ofdrugs across mucosal surfaces into the circulation while causing lessirritation, burning sensation or other local toxicity than is acharacteristic by-product of transport facilitaion by other carriermolecules.

The invention also allows drug administration to be tailored much moreclosely to cyclic disease states than is possible with other forms ofadministration. This is of particular importance with diseases (such asdiabetes) in which drug requirements vary during the course of a day.

It is contemplated that the adjuvants and methods of the instantinvention can be used to administer agents useful for vaccination (bothactive immunization with antigens and immunogenic fragments thereof aswell as passive immunization with antibodies and neutralizing fragmentsthereof) and to administer agents useful for birth control.

It is further contemplated that the adjuvants and methods of the instantinvention may potentially be useful for the delivery across plantsurfaces of antiviral agents, systemic insecticides and herbicides; andacross arthropod surface of contact insecticides and miticides.

Other features and advantages of the invention will be apparent from thefollowing description of the preferred embodiments thereof, and from theclaims.

DESCRIPTION OF THE INVENTION

The steroid which is admixed with a drug to be administered ispreferably an ionized or partially ionized, water-soluble derivative offusidic acid or cephalosporin P₁ -P₅, preferably a derivative havingformula (1), above. These steroid molecules are all characterized inthat they have the specific four-ring structure of fusidic acid andcephalosporin P₁ -P₅, including the boat conformation of the B ring (incontrast to cholesterol derivatives such as bile salts, which have the Bring in the lower energy, more stable chair conformation).

The structure of the steroid molecule affects its chemical propertiesand thus its functioning as a drug transporting molecule. We believethat all of the steroid molecules used in the invention facilitatetransport by self-associating to form reversed micelles within themembrane across which the drug is being transported; these reversedmicelles, it is believed, function as pores, allowing the drug to passthrough. A measure of a given steroid molecule's ability to form suchreversed micelles is the hydrophobicity of the unconjugated form of themolecule, a property which can be quantified using the k' factor value,which is computed by observing the steroid's retention time in ahigh-performance liquid chromatography (HPLC) column under theconditions described above. As mentioned above, the k' value of theunconjugated derivative of the steroid should be at least about 4 forthe steroid to be suitable in the therapeutic compositions of theinvention.

Critical micellar temperature (CMT) is an additional measure of asteroid's utility in the compositions of the invention. CMT is thetemperature at which the steroid molecules abruptly become soluble andself-associate into micelles from the gel or crystalline state. Thischange is a reflection of the colligative properties of the system, andthe micelles formed at a temperature just above the CMT can be small,e.g. dimers. The steroid molecules used in the invention should have agreat enough tendency to self-associate to give a CMT at or below humanor animal body temperature and optimally below about 0° C., for a 1%aqueous solution, w/v, within the range of about pH 2 to about pH 12.

The steroids of formula (1) can be conjugated or unconjugated at C₂₁.The conjugating group can be any organic group which does not raise thecritical micellar temperature of a 1% solution of the steroid abovehuman or animal body temperature and preferably does not raise the CMTabove about 0° C. within the range of about pH 2 to about pH 12 and doesnot raise the CMC above about 8 mMolar at 37° C. in 0.15 M NaCl asmeasured by surface tension. Preferably, the CMC is less than 2 mMolarunder similar conditions.

The conjugating group can be, e.g., any ionic function-containingstraight or branch-chained amino acid. The amino acid can be aliphaticor aromatic, and can also be a homo- or a dihomo-amino acid, e.g.homotaurine or homoglycine, or an amphoteric amino acid, e.g.,sulfobetaine or phosphobetaine. A straight or branched chain di- ortripeptide which terminates in an ionic functiom which is dissociatedwithin the range of about pH 2 to about pH 12 can also be employed.Peptides larger than tripeptides generally should not be used becausethey can lead to unacceptably lower solubility. Any suitable uronicacid, e.g. glucuronic acid, can also be used.

Preferred conjugating amino acids are glycine and taurine. Preferredstraight-chain peptides are diglycine and glutathione, and preferredbranched chain peptides are sarcosylcysteine, hydroxyprolinetaurine, andsarcosyltaurine.

When the conjugating group is a polyether of at least sixteen carbonatoms, the group need not (although it may) contain an ionic function;the ionic function is unnecessary because such groups are highly polarand thus confer solubility without ionization. For smaller polyethergroups, an ionic function is generally necessary, although it can beweakly ionizable since the smaller polyethers are polar themselves.

The group bonded to each of C₆ and C₁₆, independently, (W and E informula (1)) can be OAc (OCOCH₃) as in naturally occurring fusidic acidand cephalosporin P₁. Alternatively, E can be OH, an alkyl (e.g., methylor ethyl) or a different heteroalkyl (e.g. alkyloxy, alkylthio, or etherderivative) group of three or fewer carbon atoms; larger groups canunacceptably lower solublity. Group G, bonded to C₃, can be OH, as innaturally occurring fusidic acid and cephalosporin P₁ -P₅. G can also beOAc, a lower alkyl group, or a different lower heteroalkyl group. GroupW, if OAc, preferably should be in the β-axial orientation.

The molecule should possess two or three polar functions, exclusive ofany side chain at C₂₁, at the positions indicated above where acetoxyland hydroxyl groups can be located.

The k' and CMT of the steroids used in the compositions of the inventionare influenced by whether the steroid is conjugated at C₂₁ and, if so,by the nature of the conjugating group. Additionally, a polar group atposition 16 is essential for solubility (See position E on formula 1).Because the k' factor value is influenced by the polarity of anyconjugating group, unconjugated derivatives must be used in numericalcomparisons involving steroids which are conjugated with differentgroups, or comparisons involving both conjugated and unconjugatedsteroid. Overall hydrophobicity and k' factor value generally decreaseas the polarity of the conjugating group increases. However, suchdecrease is not a reflection of the hydrophobicity of the steroidnucleus. It is this hydrophobicity which is the important parameter forpurposes of reversed micelle formation.

As discussed supra, the k' factor value of the unconjugated derivativeof any such steroid should be at least about 4. For example some k'values of some unconjugated steroids useful in the invention are:cephalosporin P₁ (k'=9.5); fusidic acid (k'=20.7); 3-acetoxyl-fusidicacid (k'=26.4); 24,25-dihydrofusidic acid (k'=27.1). To give a fewminimum k' values of conjugated steroids, the k' factor value of aglycine-conjugated steroid should be at least about 2 to be useful inthe invention. For a taurine-conjugated steroid, the k' factor valueshould be at least about 1.

It is desirable that conjugated steroids have strongly ionizedconjugating groups which are capable of forming micelles at low pH andconcentrations (the critical micellar concentration, CMC, is a measureof this latter property). As mentioned above, examples of such desirableconjugating groups include but are not limited to taurine, homotaurine,sarcosyltaurine, and sulfobetaine. Steroids conjugated with such groupsalso have the advantages of stability and ease of synthesis.

Conjugation has additional effects as well, which provide theopportunity to tailor the conjugated steroid to a given clinicalsituation. For example, if the steroid is to be used to transport a drugacross a mucosal membrane, e.g. the nasal mucosa, relatively long (e.g.homotaurine), branched (e.g. sarcosyltaurine), bulky (e.g. glucuronicacid), and amphoteric (e.g. sulfobetaine) groups are desirable, sincethey may cause the steroid to be held in the nasal membrane somewhatlonger than unconjugated steroids or steroids conjugated with smallerconjugating groups.

Conjugation also, in some instances, lowers the CMC, so that only asmall amount of steroid need be used. Strong acidic conjugating groupsrender the steroid resistant to being taken out of solution byvariations in pH, ionic strength, and by the presence of other ions(e.g. Ca⁺⁺) and other macromolecules. Conjugation further preventsretention by the body, promotes rapid excretion, and prevents hepaticmetabolism to potentially toxic metabolites (Beauaboin et al., J. Clin.Invest. (1975) 56:1431-1441).

As mentioned above, conjugating groups are bonded to C₂₁ via anysuitable linkage, e.g. amide or ester. Conjugation is carried out usingconventional techniques. As an example, taurine bonded to C₂₁ via anamide linkage is shown below (the presence of a cation, e.g. K⁺ or Na⁺,is indicated in the parentheses): ##STR2##

The properties of the steroid are also affected by the nature of thesubstituents at C₃, C₆ and C₁₆. Generally, OAc groups at these positionstend to aid solubility; however, OAc groups are also quite labile, andtend to decrease stability and shelf-life.

The fusidic acid or cephalosporin P₁ -P₅ derivatives can be made byappropriately modifying commercially available fusidic acid orcephalosporin P₁ -P₅. Such techniques are known in the art.

The drugs which are admixed with a steroid carrier preferably have amolecular weight of between about 100 daltons and about 300,000 daltons.The drug may be either water soluble or lipid soluble, and may be apeptide, e.g. a peptide hormone such as insulin or a peptide hormoneprecursor such as proinsulin. Water soluble drugs, e.g. some peptidesand vitamins, can also be transported across mucosal membranes by any ofthe steroids of the invention, including those whose unconjugatedderivatives have relatively low k' values (between about 7 and about15). For hydrophobic, lipid-soluble drugs, e.g. the lipid-solublevitamins, the unconjugated derivative of the steroid should have ahigher k' value, preferably above about 20.

Drugs for which the method of administration of the invention isparticularly important are peptides. Suitable peptides include but arenot limited to insulin, proinsulin, glucagon, parathyroid hormone andantagonists of it, calcitonin, vasopressin, renin, prolactin, growthhormone, thyroid stimulating hormone, corticotropin, folliclestimulating hormone, luteinizing hormone, chorionic gonadotropin, atrialpeptides (a natriuretic factor), interferon, tissue plasminogenactivator, gammaglobulin, Factor VIII, and chemical modifications ofthese peptides.

The invention can also be used to administer hormone releasing hormones,e.g. growth hormone releasing hormone, corticotropin releasing factor,luteinizing hormone releasing hormone, growth hormone release inhibitinghormone (somatostatin) and thyrotropin releasing hormone.

Other suitable drugs include the physiologically active enzymes:transferases, hydrolases, isomerases, proteases, ligases, andoxidoreductases such as esterases, phosphatases, glycosidases andpeptidases; enzyme inhibitors such as leupeptin, chymostatin andpepstatin; and growth factors such as tumor angiogenesis factor,epidermal growth factor, nerve growth factor and insulin-like growthfactors. Other suitable drugs are those normally absorbed to a limitedextent across the gastrointestinal mucosa after oral administration;e.g. antihistamines (e.g. diphenhydramine and chlorpheniramine), anddrugs affecting the cardiovascular (e.g., antihypertensives), renal,hepatic and immune systems (including vaccines). Additionally,sympathomimetic drugs, such as the catecholamines (e.g. epinephrine) andnon-catecholamines (e.g. phenylephrine and pseudoephedrine) may beadministered according to the method of the present invention.

Drugs such as anti-infective agents, including antibacterial, antiviraland antifungal agents may also be administered according to the methodof the present invention. For example, antibiotics such as theaminoglycosides (e.g., streptomycin, gentamicin, kanamycin, etc.) aregenerally not adequately absorbed after oral administration, and maytherefore be advantageously administered by the method of the invention.

Many other drugs may also be administered according to the invention,e.g. the many drugs currently used to treat arthritis such as narcoticpain relievers. Anti-inflammatory agents (e.g. indomethacin,dexamethasone and triamcinolone), anti-tumor agents (e.g. 5-fluorouraciland methotrexate) and tranquilizers such as diazepam may also beadministered according to the invention.

Other suitable drugs are the water insoluble, fat-soluble hydrophobicdrugs, e.g. steroids such as progesterone, estrogens (includingcontraceptives such as ethinyl estradiol) and androgens and theiranalogs, and the fat-soluble vitamins, e.g. vitamins A, D, E and K, andtheir analogs.

The surface across which transport occurs may be any mucosal surfacesuch as the nasopharynx, conjunctiva, oropharynx, ear canal, rectal,intestinal (enteral), respiratory tract, endometrial, cervical vaginal,urethra, urinary bladder or, in some circumstances, a skin surface suchas the axilla, the gluteal cleft, tympanic membrane, between the toes,and the groin. Additionally, transport of the drug according to themethod of the present invention may enhance penetration into the skinfor increased local effects.

The ratio of drug and steroid present in a therapeutic composition willvary depending on a number of factors, including the k' and CMC of thesteroid, the dosage of the drug to be administered, and the chemicalcharacteristics, e.g. hydrophobicity, of the drug. Generally, thesteroid is provided in an aqueous physiological buffer solution which isthen mixed with the drug. The solution generally contains about 0.1% toabout 2.5%, w/v, steroid in a physiologically acceptable carrier, e.g.sodium phosphate buffered NaCl, pH 5-8, having a NaCl concentration ofabout 0.05M to about 0.6M.

The concentration of the drug in the solution will of course varywidely, depending on the nature of the drug, and on the extent to whichabsorption is facilitated by the steroid. In some cases, administrationaccording to the invention will enable the delivery of a higher dosageof the drug where needed than if the conventional mode of administrationis used; in other cases, a much smaller dosage can be used because ofefficient administration to a site. For instance, the amount of drugpotentially can be decreased to one thousandth the amount or increasedto ten times the amount of the drug normally used with conventionaladministration methods.

The therapeutic composition may contain, in addition to steroid anddrug, any other desired non-toxic, pharmaceutically acceptablesubstances, e.g. a preservative such a phenol or cresol or stabilizingagents.

The dosage given at any one time will depend on a number of factorsincluding, in addition to those mentioned above, the frequency ofadministration.

The compositions of the present invention may be administered to humanand animal body surfaces in a variety of forms, including but notlimited to, sprays, drops, suppositories, douches, salves, ointments,and creams. Some compositions may be advantageously applied in long termrelease dosage forms such as slow release, continuous release andintermittent release dosage forms. These long term release dosage formsinclude but are not limited to polymers, microcapsules, microspheres,osmotic diffusion devices and membrane release devices.

EXAMPLES

The following examples are intended to illustrate the invention, withoutacting as a limitation upon its scope.

Examples 1-14 demonstrate the effectiveness of using various fusidicacid derivatives (Leo Pharmaceuticals, Ballerup, Denmark) andcephalosporin as adjuvants for the delivery of insulin, glucagon, humanchorionic gonadotropin (hCG), proinsulin, corticotropin releasing-factor(CRF) and epinephrine across nasal mucosal membranes or conjunctivalmembranes in humans or sheep. Assays of insulin, glucagon, and hCGacross nasal mucosal membranes and conjunctival membranes wereaccomplished by highly specific radioimmunoassay (RIA). (Protocols forRIA of insulin followed the procedures given in "GammaCoat [¹²⁵ I]Insulin Radioimmunoassay Kit," Cat. No. CA-532, Clinical Assays Divisionof Travenol Laboratories, Inc., Cambridge, Mass. and for glucagon, theprocedures given in "Protocol for the Radioimmunoassay of Glucagon [¹²⁵I]," Cat. No. 520, Cambridge Medical Diagnostics, Middle Billerica,Mass.) In the case of proinsulin, an insulin immunoassay withsignificant cross-reactivity for proinsulin was adapted to estimate theamounts of proinsulin absorbed. (The protocol is given in "Insulin [¹²⁵I] Radioimmunoassay," Corning Medical and Scientific, Medfield, Mass.)The values obtained for insulin were adjusted to correlate with knowncross-reactivity (i.e., 36%) of proinsulin in the assay. The "GammaDab[¹²⁵ I] β-HCG Radioimmunoassay Kit," Clinical Assays Cat. No. 589,Clinical Assays Division of Travenol Laboratories, Inc., Cambridge,Mass. was used to evaluate hCG levels in serum.

INTRANASAL ADMINISTRATION OF INSULIN TO HUMANS Example 1

The final concentration of insulin varied for each subject since theywere of different weights.

Sodium tauro-24,25-dihydrofusidate was dissolved in 0.15M NaCl, pH 7.4to form a 5% solution, w/v. Commercially available porcine regularinsulin (U-500) (Eli Lilly & Co., Indianapolis, Ind.) was mixed in atotal volume of 2.0 ml with 0.15M NaCl, pH 7.4 and the 5% solution ofsodium tauro-24,25-dihydrofusidate to give final concentrations of 216U/ml insulin and 1% (w/v) sodium tauro-24,25-dihydrofusidate. A normalhuman subject (subject 40) was administered at time 0, by nasal spray,two 75 microliter aliquots, so that the dosage of insulin administeredto the subject was 0.5 Units/kg body weight.

For subjects 92 and 93, sodium tauro-24,25-dihydrofusidate was dissolvedin 0.15M NaCl, 0.05M sodium phosphate buffer, pH 7.6 to form a 2%solution, w/v. Insulin was mixed in a total volume of 7.0 ml with the0.15M NaCl, 0.05M sodium phosphate buffer and the 2% solution of sodiumtauro-24,25-dihydrofusidate to give final concentrations of 220 Units/mlfor subject 92 and 233 Units/ml for subject 93.

As shown in Table I, below, five minutes after nasal administration,subject 40's serum insulin level had increased more than twenty-fold,demonstrating that the insulin had been rapidly and effectively absorbedacross the nasal mucosa. After ten minutes serum insulin levels forsubjects 92 and 93 had increased more than ten-fold, indicating rapidabsorption across the nasal mucosa. Furthermore, as is shown in Table I,each subjects' blood glucose was lowered significantly after twentyminutes, and was reduced more than fifty percent after thirty minutesfor subjects 40 and 92.

                  TABLE I                                                         ______________________________________                                        STUDY OF NASALLY ADMINISTERED INSULIN IN                                      SODIUM TAURO-24,25-DIHYDROFUSIDATE TO HUMANS                                                Blood     Serum     Insulin                                            Time   Glucose   Insulin   (μU/ml                                          (minutes)                                                                            (mg/dl)   (μU/ml)                                                                              above basal)                                ______________________________________                                        SUBJECT 40                                                                             -20      89.9      5.6     1.1                                                -10      88                                                                    0       89        4.5     0                                                  +5                 115     110.5                                              10       82        100     95.5                                               15                 95      90.5                                               20       54.5      62      57.5                                               25                 30                                                         30       31.5      22      17.5                                               40       37.5      10      5.5                                                50       50        6.4     1.9                                                60       72        8.8     4.3                                                75       85        5                                                          90       89        3.5                                               SUBJECT 92                                                                             -20      81        5.0     .3                                                  0       80        4.7     0                                                  +5       79.5      52      47.3                                               10       74.5      68      63.3                                               15       61.5      55      50.3                                               20       47        35      30.3                                               30       34.5                                                                 40       53.5      6.4     1.7                                                50       67        3.2     0                                                  60       71.5      2.8     0                                         SUBJECT 93                                                                             -20      91.5      7.2     1.8                                                 0       89        5.4     0                                                  +5       89.5      54      48.6                                               10       85        58      52.6                                               15       75.5      28.5    23.1                                               20       66        19.5    14.1                                               30       65.5      7.2     1.8                                                40       75        4.7     0                                                  50       84.5      9.4     4.0                                                60       84.5      6.2     0.8                                       ______________________________________                                    

Example 2

Unconjugated sodium fusidate was dissolved in 0.15M NaCl, pH 7.4 to forma 3% solution w/v. Commercially available insulin (U-500) was mixed in atotal volume of 3 ml with 0.15M NaCl, pH 7.4 and the 3% solution ofsodium fusidate to give final concentrations of 210 Units/ml insulin and1% (w/v) sodium fusidate. A normal human subject was administered theinsulin preparation by nasal spray at time 0 as described in Example 1.The results obtained are shown in Table II below. Twenty minutes afternasal administration the subject's serum insulin level had increasedmore than fifteen-fold. Additionally, as is shown in Table II, thesubject's blood glucose was reduced more than fifty percent after thirtyminutes.

                  TABLE II                                                        ______________________________________                                        STUDY OF NASALLY ADMINISTERED INSULIN IN                                      UNCONJUGATED SODIUM FUSIDATE, pH 7.4 TO                                       HUMANS                                                                                       Blood     Serum    Insulin                                            Time    Glucose   Insulin  (μU/ml                                          (minutes)                                                                             (mg/dl)   (μU/ml)                                                                             above basal)                                ______________________________________                                        SUBJECT 33                                                                             -20       75.5      3.7    -.8                                                0         79        4.5    0                                                  +5                  16     11.5                                               10        77        60     55.5                                               15                  80     75.5                                               20        59.5      85     80.5                                               30        34        28     23.5                                               40        43.5      10.5   6                                                  50        56.5      7       2.5                                               60        68.5      4.5    0                                         ______________________________________                                    

Example 3

The insulin preparation was obtained by the same procedure as describedin Example 2. However, the pH of the solution was adjusted to pH 7.95and the final insulin concentration was 267 Units/ml. A normal humansubject was administered the insulin preparation by nasal spray at time0 as described in Example 1. As shown in Table III below the subject'sserum insulin level had increased more than thirty-five fold afterfifteen minutes. Furthermore the patient's blood glucose was loweredsignificantly after thirty minutes.

                  TABLE III                                                       ______________________________________                                        STUDY OF NASALLY ADMINISTERED INSULIN IN                                      UNCONJUGATED SODIUM FUSIDATE, pH 7.95 TO                                      HUMANS                                                                                       Blood     Serum    Insulin                                            Time    Glucose   Insulin  (μU/ml                                          (minutes)                                                                             (mg/dl)   (μU/ml)                                                                             above basal)                                ______________________________________                                        SUBJECT 35                                                                             -20                 1.7    0                                                   0        80        1.7    0                                                  +5                  45     43.3                                               10        80        60     58.3                                               15                  34     32.3                                               20        64        20     18.3                                               30        46        10     8.3                                                40        56        4.5    2.8                                                50        73.5      14     12.3                                               60        84        7      5.3                                       ______________________________________                                    

Example 4

Sodium glyco-24,25-dihydrofusidate was dissolved in 0.15M NaCl, pH 7.6to form a 3% solution w/v. Commercially available porcine insulin(U-500) was mixed in a total volume of 3.0 ml with 0.15M NaCl, pH 7.6and the 3% solution of sodium glyco-24,25-dihydrofusidate to give finalconcentrations of 216 Units/ml insulin and 1% (w/v) sodiumglyco-24,25-dihydrofusidate. Subject 40 was administered the insulinpreparation by nasal spray at time 0 as described in Example 1. As shownin Table IV below, five minutes after nasal administration, subject 40'sserum insulin had increased more than twenty-fold, indicating that theinsulin had been rapidly and effectively absorbed through the nasalmucosa. Furthermore, the subject's blood glucose was loweredsignificantly after twenty minutes.

                  TABLE IV                                                        ______________________________________                                        STUDY OF NASALLY ADMINISTERED INSULIN IN                                      SODIUM GLYCO-24,25-DIHYDROFUSIDATE TO HUMANS                                                 Blood     Serum    Insulin                                            Time    Glucose   Insulin  (μU/ml                                          (minutes)                                                                             (mg/dl)   (μU/ml)                                                                             above basal)                                ______________________________________                                        SUBJECT 40                                                                             -20       90        3.5     .8                                                 0        86.5      2.7    0                                                  +5                  66     63.3                                               10        81        58     55.3                                               15                  38     35.3                                               20        60        23     20.3                                               30        51        6       3.3                                               40        67.5      4.5     1.8                                               50        78.5      5.6     2.9                                               60        82.5      2.4    -.3                                       ______________________________________                                    

Example 5

For subject 34, sodium 24,25-dihydrofusidate was dissolved in 0.15MNaCl, pH 8.1 to form a 3% solution w/v. Commercially available porcineinsulin (U-500) was mixed in a total volume of 3 ml with 0.15M NaCl, pH8.1, and the 3% solution of sodium 24,25-dihydrofusidate to give finalconcentrations of 190 Units/ml insulin and 1% (w/v) sodium24,25-dihydrofusidate. For subject 35, the insulin preparation was madein the same manner as described above except that the initial sodium24,25-dihydrofusidate concentration was 3.75% (w/v) and the finalinsulin concentration was 267 Units/ml. The two normal human subjectswere administered the insulin preparation by nasal spray at time 0 asdescribed in Example 1. As shown in Table V below, fifteen minutes afternasal administration subject 34's serum insulin level had increasedthirty-fold and the subject's blood glucose was lowered significantlyafter thirty minutes. Subject 35 showed a dramatic increase in seruminsulin (63.5-fold) after ten minutes, demonstrating that the insulinhad been rapidly and effectively absorbed through the nasal mucosa.Additionally, the subjects' blood glucose was lowered more than fiftypercent after thirty minutes.

                  TABLE V                                                         ______________________________________                                        STUDY OF NASALLY ADMINISTERED INSULIN                                         IN SODIUM 24,25-DIHYDROFUSIDATE TO HUMANS                                                    Blood     Serum    Insulin                                            Time    Glucose   Insulin  (μU/ml                                          (minutes)                                                                             (mg/dl)   (μU/ml)                                                                             above basal)                                ______________________________________                                        SUBJECT 34                                                                             -20       76        2.2     .3                                                 0        76.5      1.9    0                                                  +5                  9.6     7.7                                               10        79        36     34.1                                               15                  38     36.1                                               20        65.5      28     26.1                                               30        49        9.6     7.7                                               40        44.5      7       5.1                                               50        52.5      3       1.1                                               60        69        2      1                                         SUBJECT 35                                                                             -20       75.5      1.6    -1                                                  0        76.5      2.6    0                                                  +5                  94     91.4                                               10        72        165    162.4                                              15                  130    127.4                                              20        42.5      98     95.4                                               30        21.5      37     34.4                                               40        29        8.4     5.8                                               50        44        6.4     3.8                                               60        54.5      3.5     .9                                       ______________________________________                                    

Example 6

Cephalosporin P₁ was dissolved in 0.15M NaCl, pH 7.6 to form a 5%solution, w/v. Commercially available insulin was mixed with 0.15M NaCl,pH 7.6 and the 5% solution of cephalosporin P₁ to give finalconcentrations of 220 Units/ml insulin and 1% (w/v) cephalosporin P₁. Ahuman subject was administered, by nasal spray two 75 microliteraliquots (33 Units) at time 0 so that the dosage of insulin administeredto the subject was 0.5 Units/kg body weight.

As shown in Table VI, the subject's blood glucose level decreasedslightly. Serum insulin levels are not yet available.

                  TABLE VI                                                        ______________________________________                                        STUDY OF NASALLY ADMINISTERED INSULIN                                         IN CEPHALOSPORIN P.sub.1 TO HUMANS                                                           Blood                                                          Time           Glucose                                                        (minutes)      (mg/dl)                                                        ______________________________________                                        -15            96                                                              0             97.5                                                           +5             92                                                             10             91                                                             15             90.5                                                           20             86.5                                                           30             76.5                                                           45             82.5                                                           60             88.5                                                           ______________________________________                                    

CONJUNCTIVAL ADMINISTRATION OF INSULIN TO SHEEP Example 7

Sodium tauro-24,25-dihydrofusidate was dissolved in 0.15M NaCl, 0.05Msodium phosphate buffer, pH 7.6 to form a 2% solution, w/v. Porcineinsulin (U-500) was mixed in a total volume of 1 ml with 0.15M NaCl,0.05M sodium phosphate buffer, pH 7.6 and the 2% solution of sodiumtauro-24,25-dihydrofusidate to give final concentrations of 97.5Units/ml insulin and 1% (w/v) sodium tauro-24,25-dihydrofusidate. Twosheep were administered 350 mg ketamine (a general anesthetic)intravenously and 1.0 Unit/kg body weight of insulin to the conjunctivalsac as drops at time 0. As shown in Table VII below, five minutes afterconjunctival administration, the serum insulin level of both sheep hadincreased greater than five fold. Unlike human subjects, sheep do notrespond to these increments in serum insulin levels with a decrease inblood glucose concentrations.

                  TABLE VII                                                       ______________________________________                                        STUDY OF                                                                      CONJUNCTIVAL ADMINISTRATION OF INSULIN                                        IN SODIUM TAURO-24,25-DIHYDROFUSIDATE TO SHEEP                                                    Serum                                                                  Time   Insulin                                                                (minutes)                                                                            (μU/ml)                                                ______________________________________                                        Sheep A        -15      24                                                    -5             30                                                                            0        24.5                                                                 +5       >200                                                                 10       >200                                                                 15       >200                                                                 20       190                                                                  30       >200                                                                 45       195                                                                  60       125                                                                  75       70                                                                   90       180                                                   Sheep B        -15      22                                                                   -5       22                                                                   0        42                                                                   +5       >200                                                                 10       >200                                                                 15       49                                                                   20       35                                                                   30       58                                                                   45       160                                                                  60       82                                                    ______________________________________                                    

INTRANASAL ADMINISTRATION OF GLUCAGON TO SHEEP Example 8

Sodium tauro-24,25-dihydrofusidate was dissolved in 0.15M NaCl, 0.5Msodium phosphate, pH 7.6. The dry powder of bovine glucagon (Eli Lilly &Co., Indianapolis, Ind.) was dissolved in the fusidate buffer to a finalconcentration of 1 mg/ml, pH 7.6. A sheep was administered 350 mgketamine intravenously and 200 μl of the glucagon solution wasadministered as a liquid at time 0, by drops into each side of the noseof the sheep. The dose of glucagon was approximately 10 μg/kg bodyweight.

Serum glucagon levels were determined as shown in Table VIII. Fiveminutes after intranasal administration, the glucagon level hadincreased more than one hundred-twenty fold demonstrating that theglucagon had been rapidly and effectively absorbed through the nasalmucosa.

Glucagon was also administered to the nasal mucosa without adjuvant.However, no direct control studies were performed since glucagon isrelatively insoluble at neutral pH. Instead, studies were performed aswith the adjuvant, at pH 2.7. 420 μg glucagon was dissolved in 0.002NHCl to administer the same concentration of material as described above.200 μg of glucagon was administered to each side of the nose at time 0.Glucagon was absorbed across the nasal mucosa without adjuvant at pH2.7. However, the percentage of increment was not as great withoutadjuvant as with adjuvant.

                  TABLE VIII                                                      ______________________________________                                        STUDY OF                                                                      NASALLY ADMINISTERED GLUCAGON WITH OR                                         WITHOUT SODIUM TAURO-24,25-DIHYDROFUSIDATE TO                                 SHEEP                                                                                       Time   Glucagon                                                               (minutes)                                                                            (pg/ml)                                                  ______________________________________                                        SHEEP 412.sup.a -15       16                                                                  -5        16                                                                   0        30                                                                  +5       3800                                                                 10       1150                                                                 15       660                                                                  20       340                                                                  30       110                                                                  45       130                                                                  60        80                                                                  75       105                                                                  90        54                                                  SHEEP 412.sup.b -15      210                                                                  -5                                                                             0       450                                                                  +5       4900                                                                 10       3300                                                                 15       1700                                                                 20       960                                                                  30       680                                                                  45       580                                                                  60       800                                                  ______________________________________                                         .sup.a Sodium tauro24,25-dihydrofusidate (pH 7.6)                             .sup.b No sodium tauro24,25-dihydrofusidate (highly acidic pH of 2.7 was      necessary to dissolve glucagon at sufficient concentration for                administration)                                                          

CONJUNCTIVAL ADMINISTRATION OF GLUCAGON IN SHEEP Example 9

Sodium tauro-24,25-dihydrofusidate was dissolved in 0.15M NaCl, 0.05Msodium phosphate, pH 7.6. Bovine glucagon was dissolved in the fusidatecontaining buffer to a final concentration of 1 mg/ml, pH 7.6. A sheepwas administered 350 mg ketamine intravenously and a total of 400 μg ofthe glucagon was administered to the conjunctivae in the presence (pH7.6) and absence (pH 2.7) of adjuvant at time 0 and 90, respectively. Asdescribed in Table IX below, in the presence of the adjuvant, glucagonwas absorbed across the conjunctival mucosa. Since glucagon isrelatively insoluble at neutral pH, no direct control studies wereperformed. However, in the absence of the adjuvant, glucagon wasdissolved in 0.002N HCl, pH 2.7, as described in Example 8 above. Thestudies indicated that glucagon was not absorbed across the conjunctivalmucosa to a significant extent.

                  TABLE IX                                                        ______________________________________                                        STUDY OF CONJUNCTIVAL ADMINISTRATION                                          OF GLUCAGON WITH OR WITHOUT SODIUM                                            TAURO-24,25-DIHYDROFUSIDATE IN SHEEP                                                       Time   Glucagon                                                               (minutes)                                                                            (pg/ml)                                                   ______________________________________                                        Sheep 196.sup.a                                                                              -15      250                                                                  -5                                                                             0       180                                                                  +5       3400                                                                 10       1200                                                                 15       800                                                                  20       620                                                                  30       250                                                                  45       310                                                                  60       280                                                                  75       420                                                   Sheep 196.sup.b                                                                              90       240                                                                  95       580                                                                  100      640                                                                  105      560                                                                  110      360                                                                  120      410                                                                  135      470                                                                  150      440                                                   ______________________________________                                         .sup.a Sodium tauro24,25-dihydrofusidate (pH 7.6)                             .sup.b No sodium tauro24,25-dihydrofusidate (highly acidic pH of 2.7 was      necessary to dissolve glucagon at sufficient concentration for                administration)                                                          

NASAL ADMINISTRATION OF HUMAN CHORIONIC GONADOTROPIN IN SHEEP Example 10

Sodium tauro-24,25-dihydrofusidate was dissolved in 0.15M NaCl, 0.05Msodium phosphate, pH 7.6. Human chorionic gonadotropin (hCG, aglycoprotein of MW 39,000) (National Pituitary Agency, Baltimore, Md.)was dissolved at a concentration of 2 mg/ml in 0.15M NaCl and 0.5Msodium phosphate. The hCG was mixed with the fusidate containing bufferto a final concentration of 1%, pH 7.6. 350 mg of ketamine wasadministered intravenously and one mg of hCG was administered at time 0in the form of drops (250 μl in each nostril) of a sheep. As shown inTable X below, the data indicate that in the presence of adjuvant,significant blood levels of hCG did not appear in either animal until 20to 30 minutes after administration.

                  TABLE X                                                         ______________________________________                                        STUDY OF NASALLY ADMINISTERED HUMAN                                           CHORIONIC GONADOTROPIN IN SODIUM                                              TAURO-24,25-DIHYDROFUSIDATE IN SHEEP                                                        Time   hCG                                                                    (minutes)                                                                            (mIU/ml)                                                 ______________________________________                                        SHEEP 412       -15      1.0                                                                  -5       0                                                                    0        1.5                                                                  +5       2.5                                                                  10       4.3                                                                  15       6.4                                                                  20       10.5                                                                 30       18.0                                                                 45       19.0                                                                 60       28.0                                                                 75       32.0                                                 SHEEP 196       -15      0                                                                    5        0                                                                    0        0                                                                    +5       0                                                                    10       0                                                                    15       0                                                                    20       0                                                                    30       4.1                                                                  45       12.5                                                                 60       15.5                                                                 75       15.5                                                                 90       19.5                                                 ______________________________________                                    

INTRANASAL ADMINISTRATION OF PROINSULIN TO SHEEP Example 11

Sodium tauro-24,25-dihydrofusidate was dissolved in 0.15M NaCl, pH 7.6.Commercially available proinsulin (Eli Lilly & Co., Indianapolis, Ind.)was mixed with the sodium tauro-24,25-dihydrofusidate solution or in0.15M NaCl, pH 7.6 to give a final concentration of 6 mg/ml ofproinsulin and 1% (w/v) sodium tauro-24,25-dihydrofusidate. Sheep wereadministered by nasal drops 1.5 mg (250 μl) of the solution into eachnostril at time 0. Sheep 25 was administered proinsulin without adjuvantas described above. As shown in Table XI below, proinsulin was rapidlyabsorbed in the presence of adjuvant. However, in the absence ofadjuvant the proinsulin was absorbed at a slower rate and to a muchreduced extent.

                  TABLE XI                                                        ______________________________________                                        STUDY OF                                                                      NASALLY ADMINISTERED PROINSULIN WITH OR                                       WITHOUT SODIUM TAURO-24,25-DIHYDROFUSIDATE TO                                 SHEEP                                                                                   Time   Proinsulin                                                             (minutes)                                                                            (μU/ml above baseline)                                    ______________________________________                                        SHEEP 408.sup.a                                                                           -15      0                                                        Study 24     0       0                                                                    +5       119                                                                  10       136                                                                  15       133                                                                  30       108                                                                  60       53                                                                   90       36                                                                   120      33                                                                   180      53                                                                   240      22                                                       SHEEP 196.sup.b                                                                           -15      0                                                        Study 25     0       0                                                                    +5       0                                                                    10       2.8                                                                  15       28                                                                   20       56                                                                   30       22                                                                   60       0                                                                    90       0                                                                    120      0                                                                    180      0                                                                    240      2.8                                                      ______________________________________                                         .sup.a Sodium tauro24,25-dihydrofusidate                                      .sup.b No sodium tauro24,25-dihydrofusidate                              

CONJUNCTIVAL ADMINISTRATION OF PROINSULIN TO SHEEP EXAMPLE 12

Sodium tauro-24,25-dihydrofusidate was mixed with proinsulin asdescribed in Example 11. Sheep were administered a total ofapproximately 2.1 mg of the proinsulin solution to the conjunctiva attime 0. As indicated in Table XII below, proinsulin was rapidly absorbedacross the conjunctival membranes in the presence of sodiumtauro-24,25-dihydrofusidate.

                  TABLE XII                                                       ______________________________________                                        STUDY                                                                         OF CONJUNCTIVAL ADMINISTRATION OF PROINSULIN                                  IN SODIUM TAURO-24,25-DIHYDROFUSIDATE TO SHEEP                                          Time   Proinsulin                                                             (minutes)                                                                            (μU/ml above baseline)                                    ______________________________________                                        SHEEP 31    -15       0                                                                    0        0                                                                   +5       117                                                                  10       83                                                                   15       67                                                                   20       53                                                                   30       47                                                                   45       25                                                                   60       17                                                                   90       42                                                       ______________________________________                                    

INTRANASAL ADMINISTRATION OF CORTICOTROPIN RELEASING FACTOR EXAMPLE 13

Sodium tauro-24,25-dihydrofusidate was dissolved in 0.15M NaCl, pH 7.6to form a 2% solution, w/v. Corticotropin releasing-factor (CRF, ahormone of MW 4,000) (Dr. George Chrousos, National Institute of Health,Bethesda, Md.) was dissolved in 0.15 NaCl and mixed with the 2% solutionof sodium tauro-24,25-dihydrofusidate. CRF was also prepared withoutadjuvant. Two sheep were administered 350 mg ketamine intravenously anda total of 460 μg of CRF as a liquid, by drops into each side of thenose of the sheep at time 0. The dose of CRF was approximately 10 μg/kgbody weight. As shown in Table XIII, serum CRF levels were determinedeither with or without adjuvant. Five minutes after intranasaladministration with adjuvant, the CRF level had increased more than200-fold. In contrast, without adjuvant the CRF level increased onlyslightly. The data indicate that CRF had been rapidly and effectivelyabsorbed across the nasal mucosa.

                  TABLE XIII                                                      ______________________________________                                        STUDY OF NASALLY ADMINISTERED CORTICOTROPIN                                   RELEASING-FACTOR WITH OR WITHOUT                                              TAURO-24,25-DIHYDROFUSIDATE IN SHEEP                                          ______________________________________                                                     Time   CRF                                                                    (minutes)                                                                            (pg/ml)                                                   ______________________________________                                        SHEEP 11.sup.a  0       15-20                                                                +5       >200                                                                 10       >200                                                                 15       >200                                                                 20       >200                                                                 30       >200                                                                 45       >200                                                                 60       >200                                                                 75       >200                                                                 90       >200                                                                 120      >200                                                                 125      187                                                                  130      186                                                                  135      161                                                                  150      167                                                                  165      148                                                                  180      124                                                                  195      98                                                                   210      102                                                   SHEEP 12.sup.b  0       16-20                                                                +5       33                                                                   10       45                                                                   15       50                                                                   20       39                                                                   30       36                                                                   45       28                                                                   60       26                                                                   75       25                                                                   90       25                                                                   120      24                                                    ______________________________________                                         .sup.a Sodium tauro24,25-dihydrofusidate                                      .sup.b No sodium tauro24,25-dihydrofusidate                              

INTRANASAL ADMINISTRATION OF EPINEPHRINE TO SHEEP EXAMPLE 14

Sodium tauro-24,25-dihydrofusidate was dissolved in 0.05M sodiumphosphate buffer, pH 7.6 to form a 3% solution. Commercially availableepinephrine in solution (1:1000) (Elkins Sinn, Richmond, Va.) was mixedwith 0.1 ml of the 3% solution of sodium tauro-24,25-dihydrofusidate. Asheep was administered 350 mg ketamine intravenously and 150 μl of theepinephrine solution as drops to each nostril at time 0. The sheep wasalso administered epinephrine as described above without adjuvant at alater time.

Epinephrine levels were measured following extraction of plasma andrunning on HPLC with electrochemical detection.

As shown in Table XIV below, in the presence of adjuvant, epinephrinewas absorbed across the nasal mucosa to a greater extent than withoutadjuvant.

                  TABLE XIV                                                       ______________________________________                                        STUDY OF                                                                      NASAL ADMINISTRATION OF EPINEPHRINE WITH OR                                   WITHOUT SODIUM TAURO-24,25-DIHYDROFUSIDATE IN                                 SHEEP                                                                                      Time   Epinephrine                                                            (minutes)                                                                            (pg/ml)                                                   ______________________________________                                        SHEEP 412.sup.a                                                                               0        33                                                                  +5        86                                                                  10       134                                                                  15        65                                                                  30        78                                                   SHEEP 412.sup.b                                                                               0       102                                                                  +5       323                                                                  10       190                                                                  15       229                                                                  30       284                                                   ______________________________________                                         .sup.a No sodium tauro24,25-dihydrofusidate                                   .sup.b Sodium tauro24,25-dihydrofusidate                                 

It is apparent that many modifications and variations of this inventionas herein above set forth may be made without departing from the spiritand scope thereof. The specific embodiments described are given by wayof example only and the invention is limited only by the terms of theappended claims.

We claim:
 1. In a method of administering a drug which comprisesapplying to a human or animal mucosal surface for absorption across saidmucosal surfaceas an active ingredient, a biologically-effective amountof a drug specific for the disorder or condition the improvementcomprising applying the drug to the mucosal surface in admixture with abiocompatible, water-soluble, fusidic acid derivative having theformula: ##STR3## wherein a dashed line represents a single or a doublebond; D represents a group having a molecular weight below about 600daltons which renders an effective amount of said steroid water-solublewithin a range of about pH 2 to about pH 12; E and G each represent OAc,OH, a lower alkyl group or a lower heteroalkyl group; W represents OAcor H; and Q, V and X each represent H or OH,said steroid containing fromtwo to three polar functions, exclusive of the function represented byD, which biocompatible, water-soluble, fusidic acid derivative acts asan adjuvant being capable of increasing drug permeability of a human oranimal body surface across which the drug is to be administered, in anamount effective to increase the permeability of said surface to saiddrug.
 2. The method of claim 1 wherein the mucosal surface is a nasalmucosal surface.
 3. The method of claim 1 wherein the mucosal surface isa conjunctival surface.
 4. The method of claim 1 wherein the mucosalsurface is an oropharyngeal, nasopharyngeal or respiratory tractsurface.
 5. The method of claim 1 wherein the mucosal surface is avaginal, cervical or endometrial surface.
 6. The method of claim 1wherein the mucosal surface is a rectal, colonic, gastric or intestinalsurface.
 7. The method of claim 1 wherein the mucosal surface is aurethral or urinary bladder surface.
 8. The method of claim 1 whereinthe human or animal body surface is an epithelial surface.
 9. The methodof claim 1 wherein the human or animal body surface is an ear canal ortympanic membrane surface.
 10. The method of claim 1 wherein thecomposition is applied in the form of a nasal spray or nose drops. 11.The method of claim 1 wherein the composition is applied in the form ofeye drops.
 12. The method of claim 1 wherein the composition is appliedin the form of a suppository.
 13. The method of claim 1 wherein thecomposition is applied in the form of a spray, salve, ointment or cream.14. The method of claim 1 wherein the drug is epinephrine.
 15. Themethod of claim 14 wherein the epinephrine is applied to a nasal mucosalsurface in the form of a nasal spray or nose drops.
 16. The method ofclaim 1 wherein the composition is applied in a long term release dosageform.
 17. The method of claim 16 wherein the long term release dosageform is a slow, continuous or intermittent form.
 18. The method of claim16 wherein the long term release dosage form is selected from the groupconsisting of a polymer form, a microcapsule form, a microsphere form,an osmotic diffusion device or a membrane release device.
 19. The methodof claim 1 wherein the drug is an antibiotic.